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Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy.

ABSTRACT: Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

SUBMITTER: Russell AJ

PROVIDER: S-EPMC10178848 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy.

Russell Alan J AJ DuVall Mike M Barthel Ben B Qian Ying Y Peter Angela K AK Newell-Stamper Breanne L BL Hunt Kevin K Lehman Sarah S Madden Molly M Schlachter Stephen S Robertson Ben B Van Deusen Ashleigh A Rodriguez Hector M HM Vera Carlos C Su Yu Y Claflin Dennis R DR Brooks Susan V SV Nghiem Peter P Rutledge Alexis A Juehne Twlya I TI Yu Jinsheng J Barton Elisabeth R ER Luo Yangyi E YE Patsalos Andreas A Nagy Laszlo L Sweeney H Lee HL Leinwand Leslie A LA Koch Kevin K

The Journal of clinical investigation 20230515 10

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, h ...[more]

PMID: 36995778

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Project description:Background: Animal models of Duchenne muscular dystrophy (DMD) are essential to study disease progression and assess efficacy of therapeutic intervention, however dystrophic mice fail to display a clinically relevant phenotype, limiting translational utility. Dystrophin-deficient dogs exhibit disease similar to humans, making them increasingly important for late-stage preclinical evaluation of candidate therapeutics. The DE50-MD canine model of DMD carries a mutation within a human 'hotspot' region of the dystrophin gene, amenable to exon-skipping and gene editing strategies. As part of a large natural history study of disease progression, we have characterised the DE50-MD skeletal muscle phenotype to identify parameters that could serve as efficacy biomarkers in future preclinical trials. Methods: Vastus lateralis muscles were biopsied from a large cohort of DE50-MD dogs and healthy male littermates at 3-monthly intervals (3-18 months) for longitudinal analysis, with multiple muscles collected post-mortem to evaluate body-wide changes. Pathology was characterised quantitatively using histology and measurement of gene expression to determine statistical power and sample sizes appropriate for future work. Results: DE50-MD skeletal muscle exhibits widespread degeneration/regeneration, fibrosis, atrophy and inflammation. Degenerative/inflammatory changes peak during the first year of life, while fibrotic remodelling appears more gradual. Pathology is similar in most skeletal muscles, but in the diaphragm, fibrosis is more prominent, associated with fibre splitting and pathological hypertrophy. Picrosirius red and acid phosphatase staining represent useful quantitative histological biomarkers for fibrosis and inflammation respectively, while qPCR can be used to measure regeneration ( MYH3, MYH8), fibrosis ( COL1A1), inflammation ( SPP1), and stability of DE50-MD dp427 transcripts. Conclusion: The DE50-MD dog is a valuable model of DMD, with pathological features similar to young, ambulant human patients. Sample size and power calculations show that our panel of muscle biomarkers are of strong pre-clinical value, able to detect therapeutic improvements of even 25%, using trials with only six animals per group.

Dataset Information

Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy.

Publications

Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy.

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